Sigma receptors are saturable, high affinity binding sites for several important classes of psychotropic drugs, including typical antipsychotic, antidepressant, anticonvulsant, and psychotomimetic compounds. They are likely to contribute to the beneficial and/or side-effect profile of these compounds. Sigma sites are present not only in the central nervous system but also occur in several peripheral tissues, and are expressed in high density in a number of tumor cell lines. Furthermore, they are more highly expressed in rapidly proliferating cells than in quiescent cells. They may thus play an important role in cell function. Our studies have shown that sigma receptor ligands induce morphological changes, followed by apoptotic cell death in both human SK-N-SH neuroblastoma cells and primary cultures of rat cerebellar granule cells. These effects were found to be mediated by sigma-2 receptors. Activation of sigma-2 receptors was also found to cause a rise in intracellular free calcium concentration ([Ca++]i) in the neuroblastoma cells. Sigma-2 receptor agonists caused a rapid and transient rise in [Ca++]i followed, upon continued exposure of cells to compound, by a latent and sustained rise in [Ca++]i. The rapid, transient rise in [Ca++]i was found to derive from the endoplasmic reticulum, while the latent, sustained rise in [Ca++]i derives from the mitochondria. Studies are continuing in order to determine the mechanism of generation of these two calcium signals and any relationship to sigma receptor-dependent morphological changes and induction of apoptosis. The results suggest that sigma receptors may comprise novel components of the apoptotic pathway and may play an important role in regulation of cell proliferation. Other ongoing projects investigated the possible use of sigma receptors as targets for the development of non-invasive tumor imaging agents. Iodinated and Tc99m-labeled sigma receptor ligands in the benzamide, arylethylene diamine, and aryl sulfonamide structural classes were investigated in terms of biodistribution among normal tissues and ability to image solid tumor implants in nude mice. The ability to facilitate tumor imaging, in conjunction with the ability to induce apoptotic cell death suggests that sigma receptors in tumors could serve as targets for the development of both diagnostic and therapeutic agents for managing cancer.